Open Access

Advances in Ca2+ modulation of gastrointestinal anion secretion and its dysregulation in digestive disorders (Review)

  • Authors:
    • Weixi Shan
    • Yanxia Hu
    • Jianhong Ding
    • Xiaoxu Yang
    • Jun Lou
    • Qian Du
    • Qiushi Liao
    • Lihong Luo
    • Jingyu Xu
    • Rui Xie
  • View Affiliations

  • Published online on: August 25, 2020     https://doi.org/10.3892/etm.2020.9136
  • Article Number: 8
  • Copyright: © Shan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Intracellular calcium (Ca2+) is a critical cell signaling component in gastrointestinal (GI) physiology. Cytosolic calcium ([Ca2+]cyt), as a secondary messenger, controls GI epithelial fluid and ion transport, mucus and neuropeptide secretion, as well as synaptic transmission and motility. The key roles of Ca2+ signaling in other types of secretory cell (including those in the airways and salivary glands) are well known. However, its action in GI epithelial secretion and the underlying molecular mechanisms have remained to be fully elucidated. The present review focused on the role of [Ca2+]cyt in GI epithelial anion secretion. Ca2+ signaling regulates the activities of ion channels and transporters involved in GI epithelial ion and fluid transport, including Cl channels, Ca2+‑activated K+ channels, cystic fibrosis (CF) transmembrane conductance regulator and anion/HCO3 exchangers. Previous studies by the current researchers have focused on this field over several years, providing solid evidence that Ca2+ signaling has an important role in the regulation of GI epithelial anion secretion and uncovering underlying molecular mechanisms. The present review is largely based on previous studies by the current researchers and provides an overview of the currently known molecular mechanisms of GI epithelial anion secretion with an emphasis on Ca2+‑mediated ion secretion and its dysregulation in GI disorders. In addition, previous studies by the current researchers demonstrated that different regulatory mechanisms are in place for GI epithelial HCO3 and Cl secretion. An increased understanding of the roles of Ca2+ signaling and its targets in GI anion secretion may lead to the development of novel strategies to inhibit GI diseases, including the enhancement of fluid secretion in CF and protection of the GI mucosa in ulcer diseases.

1. Introduction

It is well known that [Ca2+]cyt has an essential role in numerous important mammalian cell functions, including neurotransmitter release, gene regulation, muscle contraction, cell proliferation, differentiation and apoptosis (1). Since the function of [Ca2+]cyt as the cell's secondary messenger is based on the presence of a concentration gradient between [Ca2+]cyt and external Ca2+ ([Ca2+]ext) (2), normal [Ca2+]cyt homeostasis is important. Under normal physiological conditions, the concentration of [Ca2+]cyt is <100 nM, which is ~10,000 times lower than [Ca2+]ext (>1 mM) (3,4). Furthermore, the membrane potential of ~-60 mV adds to the large electrochemical gradient and this huge concentration gradient favors the entry of Ca2+ into cells (5). Therefore, when cells are activated, Ca2+ is transported down this electrochemical gradient into the cells through the specific transmembrane Ca2+ channels, leading to increases in the [Ca2+]cyt (5).

To restore the resting levels of [Ca2+]cyt, Ca2+ is transported back to the extracellular space or stored in intracellular Ca2+ pools by Ca2+ pumps and transporters (6,7). Furthermore, [Ca2+]cyt exhibits differences functions in different type of cells (8). These are key factors that determine different specific Ca2+-dependent cellular responses affected by complex, spatiotemporal variations in [Ca2+]cyt (Fig. 1). A major determinant of these variations are different functionally distinct membrane calcium channels and exchangers, such as the receptor-operated calcium channels, voltage-gated channels, Na+/Ca2+ exchangers (NCX) and calcium pumps (9). In addition, the intracellular stores are an important determinant for Ca2+ release (10). To date, the ryanodine receptor (RyR) and inositol triphosphate receptor (IP3R) channels on the endoplasmic reticulum (ER), have been identified, which lead to Ca2+-induced Ca2+ release (CICR) or release of IP3, respectively, to mediate the release of Ca2+ from intracellular stores and increasing the [Ca2+]cyt (11).

In the digestive system, [Ca2+]cyt also has critical roles in the regulation of digestive functions (12,13). This includes GI motility and ion transport, food digestion and nutrient absorption (14). In the epithelial cells of the GI tract, ion secretion and absorption of electrolytes and fluid are two essential functions and ion transport is also a critical physiological process in the human GI tract (15). GI epithelium secretes anions (Cl- and HCO3-), providing the driving force for fluid transport to maintain fluid homeostasis in the human body (16). GI epithelial anion secretion is controlled by several neuro-humoral factors, including prostaglandin E2 (PGE2), acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) (17). These factors mediate epithelial anion secretion mainly through Ca2+, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways (17).

The physiological roles and molecular mechanisms of cAMP- and cGMP-dependent regulation of GI epithelial anion secretion have been extensively defined (18). Since certain adenylyl cyclase subtypes are Ca2+-dependent and multiple interactions between Ca2+ and cAMP signaling pathways exist in mammalian cells, it was previously thought that Ca2+ may mediate epithelial anion secretion indirectly through cAMP signaling (19).

However, various lines of evidence indicate that Ca2+ signaling is able to mediate epithelial anion secretion in a cAMP-independent manner (19,20). Although the critical role of Ca2+-dependent regulation has been verified, the underlying regulatory mechanisms remain to be fully elucidated. The current researchers have been investigating the Ca2+-mediated regulation of anion secretion by GI epithelium and provided solid evidence for a regulatory role of Ca2+ signaling in a cAMP-independent manner, as well as the underlying molecular mechanisms (19).

While the critical role of Ca2+ signaling in other types of secretory cell (such as those of the airways and salivary gland) is well known (21), the roles of Ca2+ signaling in GI epithelial secretion and its molecular mechanisms have remained to be fully elucidated. Further research is required to molecularly identify the Ca2+-activated ion transporters in GI epithelial cells. In addition, the application of muscarinic agonists was observed to lead to an increase in [Ca2+]cyt in secretory cells and promote GI anion secretion (22). However, this phenomenon has been extensively studied in other types secretory cells, such as the secretory cells in the avian basal gland (21).

Overall, the Ca2+ signaling and anion secretion mechanisms are of important clinical relevance and need to be further elucidated. In cystic fibrosis (CF), certain calcium agonists stimulate Ca2+-activated Cl- channel (CaCC)-dependent and CF transmembrane conductance regulator (CFTR)-independent secretion and agents that stimulate Ca2+ signaling may be used therapeutically to restore ion and fluid secretion defects (23). Conversely, in certain other types of GI disease, such as intestinal inflammation and diarrhea, inhibition of intracellular Ca2+ signaling may have therapeutic potential to ameliorate excessive fluid secretion (24,25) (Table I). Therefore, in the present review, the current state of knowledge regarding Ca2+ signaling in the regulation of GI epithelial anion secretion and the associated GI disorders was summarized.

Table I

Ca2+-mediated GI epithelial anion secretion and the membrane ion channels involved.

Table I

Ca2+-mediated GI epithelial anion secretion and the membrane ion channels involved.

Ion channelMechanismExpressionRelated diseasesAuthor (refs)
HCO3-Maintenance of intestinal barrier function. Mechanisms of mucosal protection. Establishes and maintains optimal pH for the activity of luminal digestive enzymesGI epithelial cellsIntestinal inflammation, peptic ulcers, acute infectious diarrhea, metabolic acidosis, CF, obstruction of the pancreatic duct, exocrine pancreatic insufficiency, CLD, IBDChen et al (26) Fei et al (36) Kuna et al (38) Gennari et al (40) Ramos et al (45)
Cl-Transports the secreted fluid from the lateral base to the apical side of intestinal cellsBasolateral GI epithelial cellsAcute infectious diarrhea, metabolic acidosis, CLD, IBDFrizzell et al (27) Mohammad- Panah et al (49)
CFTRContributes to the secretion of anions and fluids in enterotoxin-induced secretory diarrheaPancreas, epithelial cells in airways, intestinal tractCFGoodman et al (66) Deachapunya et al (67)
CaCCMay participate in anion secretion in the mammalian GI epitheliumIntestinal tractCFCaputo et al (76) Yang et al (17) Morris et al (79) Kunzelmann et al (83)
Anion/ HCO3- exchangersProtects gastric mucosa by combating aggressive factorsApical membrane of intestinal epithelial cellsAcute infectious diarrhea, metabolic acidosis, IBD, CLD, CFSingh et al (92) Tang et al (59) Smith et al (94)
SOC and STIM/Orai channelsGene expression, cell growth and organ developmentIntestinal epithelial cellsCFRao et al (105) Onodera et al (106)
KCaContributes to the stabilization of membrane voltage and provides the driving force for electrogenic anion transportIntestinal epitheliumCLD, IBD, secretory diarrhea, CFJulio-Kalajzić et al (114) Dong et al (121,127) Xie et al (13) Assaha et al (115) Wang et al (116)
NCXMaintenance of Ca2+ homeostasis in a variety of tissues. Involved in the Ca2+-dependent anion secretionCardiomyocytes, vascular cells, neurons, small intestinal epithelial cellsIntestinal inflammation, acute infectious diarrhea, metabolic acidosis, CF, CLD, IBDLee et al (124) Seipet al (126) Dong et al (121,127) Kocks et al (110)

[i] GI, gastrointestinal; HCO3-, bicarbonate; CF, cystic fibrosis; CLD, congenital chloride diarrhea; IBD, inflammatory bowel disease; Cl-, chloride; CFTR, cystic fibrosis transmembrane conductance regulator; CaCC, Ca2+-activated Cl- channel; SOC, store-operated calcium channels; STIM, stromal interaction molecule; Orai, ORAI calcium release-activated calcium modulators; KCa, Ca2+-activated K+ channel; NCX, Na+/Ca2+ exchangers.

2. General aspects of GI epithelial anion secretion

GI epithelial HCO3- secretion

GI epithelial bicarbonate (HCO3-) is produced on the surface GI epithelial cells and secreted to the luminal side of the epithelium; it isinvolved in the formation of gastrointestinal mucus with a slightly alkaline pH (12). The basolateral side of electroneutral Na+-coupled HCO3- cotransporter is one of the important transporters for HCO3- absorption (12). With the help of the carbonic anhydrase, the HCO3- is taken up and it is also generated inside the cells (26).

To date, several pathways for the export ofHCO3- into the luminal side of the GI mucosa have been elucidated: i) The CFTR or the CaCC is able to promote electrogenic HCO3- efflux, ii) luminal electroneutral anion/HCO3- exchangers have been confirmed to contribute to the transport of HCO3- and iii) HCO3- may betransported via the short-chain fatty acids (SCFA)/HCO3- exchanger in the colon (27,28). Electroneutral secretion of HCO3- is paralleled by the activity of Na+/H+ exchanger-3(29). Furthermore, the luminal Cl- channels, as a recycling pathway for Cl-, are important for HCO3- secretion and they may serve in the electrogenic secretion of HCO3- via the luminal Cl-/HCO3- antiporters (27). One of the Cl- channels, CFTR, which is located on the apical side, was clearly demonstrated to be involved in the response of HCO3- secretion in the intestine a pancreatic duct (30). Besides the CFTR, Ca2+, cAMP and cGMP were indicated to induce HCO3- secretion in the small intestine (31). Current data has also demonstrated that the CFTR is involved in the regulation of the intracellular pH and that the expression and function of Cl-/HCO3- exchangers and down-regulated in adenoma were regulated by the CFTR (32). Of note, CFTR is necessary for HCO3- secretion in numerous other epithelial tissues as well (33). Thus, it is likely that the CFTR contributes to anion secretion and control of the luminal pH in the entire GI tract, but in the mammalian colon, the SCFA-dependent HCO3- secretion is the primary mechanism of HCO3- secretion (34). Well-regulated HCO3- secretion is critical for the mucosal defense against luminal acid due to its neutralization effect in the upper GI tract and against bacteria in the lower GI tract due to its stimulation of mucus secretion and maintenance of the intestinal barrier function (35). Aside from mechanisms of mucosal protection, normal HCO3- secretion in the small intestine is assumed to establish and maintain an optimal pH for the activity of luminal digestive enzymes (35). The small intestine is in an alkaline range of pH 6.7-8.0, which is the best pH value for the optimal activity of pancreatic enzymes (36). The duodenum in particular is an important organ exerting pH control for enzymatic digestion (37).

Defective intestinal HCO3- secretion has been indicated to be a risk factor for intestinal inflammation and peptic ulcer diseases (38). Furthermore, intestinal HCO3- secretion has been critically involved in the pathophysiology of acute infectious diarrhea (39). Cholera and numerous other acute diarrheal illnesses may increase the intestinal secretion and loss of HCO3-, which may result in a severe HCO3- deficit and metabolic acidosis (40). Defective GI epithelial HCO3- secretion has been critically implicated in the pathogenesis of CF (30). A previous study examining the human duodenum indicated a CFTR-dependent alkaline transport in subjects without CF, which was absent in patients with CF (41). Furthermore, electrogenic HCO3- secretion was detected in the colon of mice without CF, while it was absent in mice with CF (42). The defective HCO3- transport in CF may be crucial for the severity of the symptoms of CF (43). Defective HCO3- transport probably causes obstruction of the pancreatic duct and exocrine pancreatic insufficiency (44). Impaired duodenal HCO3- production and failure to buffer gastric acid is responsible for an increased incidence of epigastric pain and morphological changes in the duodenum of patients with CF (45).

GI epithelial Cl- secretion

In GI physiology, fluid secretion has a critical role and is driven by active Cl- transport from the basolateral to the apical side of enterocytes (46). The basolateral Na+-K+-2Cl-cotransporter (NKCC1) is one of the important transporters for Cl- secretion (47). The rate secretion of Cl- is regulated by the activity of NKCC1, which is dependent on the intracellular Cl- concentration, cell swelling and probably phosphorylation (47). It has also been confirmed that the cAMP-activated KVLQT1/KCNE3 and Ca2+-activated K+ channels are able to maintain Cl- transport (48). The basolateral Cl- is taken up by NKCC; however, its exit is primarily via the apical CFTR. Channels such as CaCC and other Cl- channels may also take part in apical Cl- secretion (49). Na+ and water follow via a paracellular route (50). These ion and fluid transports initiated by pathogens (e.g., cholera toxin and rotavirus) involve multiple factors, such as 5-HT, substance P, ACh and vasoactive intestinal peptide, as well as the release of inflammatory mediators from mast cells and neutrophils [e.g. interleukins (ILs) and prostaglandins] (51). Ion and fluid secretion may be activated by different mechanisms that involve second messengers (cAMP, cGMP or Ca2+) to activate membrane ion channels (20).

Differences between GI epithelial secretion of Cl- and HCO3-

It is generally assumed that the GI epithelial HCO3- and Cl- secretion have the same regulatory mechanisms (52). However, this notion requires to be confirmed through a systematic comparison between them (52). As mentioned earlier, GI epithelial Cl- and HCO3- secretion is mainly controlled by cAMP and Ca2+ signaling, which may interact and cross-talk to regulate epithelial ion transport (13,27). Previous studies have demonstrated that most well-known secretagogues, including 5-HT, ACh, forskolin and PGE2, stimulate intestinal HCO3- and Cl- secretion in parallel (53-55). However, whether epithelial HCO3- and Cl- secretion occur in parallel and whether they are regulated by the same or different signaling/mechanisms currently remains elusive. Notably, it has been indicated that both forskolin- and carbachol (CCh)-induced rat colonic Cl- secretion was inhibited by estrogen (56) and further studies by the current researchers revealed that estrogen stimulates duodenal bicarbonate secretion (DBS) in humans and mice without altering basal duodenal short-circuit current (Isc), an index primarily of epithelial Cl- secretion (57,58). These results demonstrated that estrogen may have different roles in regulating intestinal HCO3- and Cl- secretion. These findings also suggest that GI epithelial HCO3- and Cl- secretion may not be necessarily triggered in the same way or by identical signaling/mechanisms. Furthermore, a previous study by the current researchers revealed that calcium-sensing receptor (CaSR) activation raises [Ca2+]cyt; however, it reduces cAMP-induced exclusive duodenal HCO3- secretion without simultaneously altering duodenal Cl- secretion (13). Similarly, Tang et al (59) demonstrated that CaSR activation stimulated colonic HCO3- secretion via SCFA/HCO3- and Cl-/HCO3- exchangers; however, it inhibited Cl-secretion via the cAMP/CFTR pathway. It may, therefore, be proposed that a different regulatory mechanism likely exists for GI epithelial HCO3- and Cl- secretion. While cAMP may have a critical role in CFTR-mediated Cl- secretion, Ca2+ signaling may be critical in anion/HCO3--mediated HCO3- secretion.

3. Ca2+ modulation of GI epithelial anion secretion

Evidence for Ca2+-mediated anion secretion

Although Ca2+ may mediate epithelial anion secretion through the cAMP signaling pathway, growing lines of evidence indicate that Ca2+ signaling is able to mediate epithelial anion secretion in a cAMP-independent manner (19). The evidence is as follows: i) The increase in [Ca2+]cyt induced by stimulation of cholinergic muscarinic type 3 receptor (M3R) were indicated to be due to activation of basolateral K+ channels, which enhanced the driving force for luminal anion exit (60); ii) Ca2+/calmodulin and protein kinase C (PKC) was demonstrated to be involved in the CCh-mediated regulation of luminal and basolateral K+ channels (61); iii) several previous studies suggested a contribution of Ca2+/PKC to CFTR activation (62,63); and iv) activation of muscarinic receptors resulted in an increase in [Ca2+]cyt; however, it decreased cAMP levels, which indeed triggered Ca2+-dependent duodenal transepithelial HCO3- secretion (13). Since cAMP-mediated ion transport has been extensively reviewed (64), the present study focused on Ca2+-mediated GI epithelial anion secretion and the membrane ion channels involved.

Apical CFTR

CFTR is expressed in different tissue types, including the pancreas, epithelial cells in the airways, GI tract and other fluid-transporting tissues (30). CF is caused by mutations in the CFTR gene, resulting in impaired Cl- and HCO3-transport and plasma membrane targeting (65). CFTR is mainly located in the luminal membrane of enterocytes and has a major role to contribute to the secretion of anions and fluid in enterotoxin-induced secretory diarrheas such as cholera (66). Numerous lines of solid evidence suggest a pivotal role for CFTR in GI anion and fluid secretion (27,30,65,66).

Numerous in vitro studies have indicated that the application of glibenclamide and 5-nitro-2-(3-phenylpropylamino) benzoic acid further inhibited the PGE2 and cAMP-mediated increase in Isc and anion secretion in GI epithelial sheets and cell lines (67,68). Mice with gene ablation of CFTR developed intestinal obstruction (69,70). The resultant characteristic ion transport impairment resulted in defective intestinal anion and fluid secretion and increased fluid absorption (71). In CFTR-null mice, increased expression of alternative Cl- channels was present and the development of mild intestinal symptoms was observed (72). Furthermore, in CFTR-knockout mice, cholera toxin failed to cause massive fluid secretion through CFTR-dependent protein (72). CFTR has long been considered a primarily cAMP-activated Cl- channel to activate GI epithelial anion secretion (30). The majority of studies have confirmed that CFTR also responds to Ca2+-mobilizing secretagogues and contributes substantially to cholinergic and purinergic responses in native tissues (30,62).

CFTR channels may be stimulated by the G protein-coupled receptor-mediated signal via Gq protein α subunit, further activating Ca2+-dependent adenylyl cyclase and tyrosine kinases, and by inhibition of protein phosphatase type 2A (PP2A) (72). For instance, the M3R couples strongly to Gαq. Stimulation of M3R produces diacylglycerol and IP3 to activate PKC and mobilize intracellular Ca2+, which in turn activates the proline-rich tyrosine kinase 2/Src complex (62). Src stimulates CFTR activity by phosphorylating it directly and inhibiting its dephosphorylation through the inactivation of PP2A (62). Under basal conditions, constitutive Ca2+ entry through store-operated Ca2+ channels partially activates adenylyl cyclase and induces tonic CFTR activity (62).

A recent in vitro study by the current researchers revealed that the stimulation of mouse duodenal Isc by CCh was significantly inhibited in a Ca2+-free solution (17). After the application of CCh, the intracellular calcium was significantly increased; however, there was no increase cAMP and compared to the CFTR-knockout mice. CCh-induced Ca2+ was involved in the duodenal Cl- and HCO3- secretion in wild-type mice. The CCh-induced intracellular calcium signaling also stimulated the phosphorylation of CFTR and promoted the CFTR transport to the plasma membrane of duodenal epithelial cells. Furthermore, CCh induced duodenal ion secretion and stimulated PI3K/Akt signaling pathway in duodenal epithelium and all of these effects were attenuated by selective PI3K inhibitors. Therefore, a novel molecular mechanism of Ca2+ signaling in CFTR-mediated ion secretion via PI3K/Akt was indicated.

Rasmussen et al (73), revealed that cigarette smoking increased [Ca2+]cyt-induced CFTR internalization, which was prevented by chelation of cytoplasmic Ca2+. Furthermore, this phenomenon was inhibited by the macrolide antibiotic bafilomycin A1, which inhibited cigarette smoking-induced Ca2+ release and prevented CFTR clearance from the plasma membrane, further linking cytoplasmic Ca2+ and CFTR internalization. Patel et al (74), also indicated that an increase in [Ca2+]cyt induced a reduction of cell surface CFTR expression. Therefore, CFTR appears to be the channel that is in charge of not cAMP-activated, Ca2+-activated Cl- and HCO3- secretion in human GI mucosa (30).

Apical CaCC

There is currently evidence that the CaCC are a further class of important Cl- channels that may participate in anion secretion in the mammalian GI epithelium (75). In luminal membranes of GI epithelia of subjects with and without CF, CaCC are stimulated by Ca2+ ionophores and Ca2+-mobilizing secretagogues (76), including acetylcholine, bradykinin, histamine, CCh and extracellular nucleotides adenosine triphosphate (ATP) and uridine triphosphate (UTP) (77,78). In mice with CF, the expression of Ca2+-dependent Cl- channels was detectable in the intestine and was age-dependent. In young mice (age, 2-3 weeks), Cl secretion was induced by carbachol in the small intestine (17). Furthermore, it was indicated that in non-CF and CF mouse pup crypts, the application of nonstructural protein 4 (NSP4) caused severe diarrhea (79). However, compared to the young CF mice, the NSP4-induced Cl- secretion was largely reduced in adult CF mice. These data further support that the expression and function of CaCC are age-dependent. Indeed, it was also revealed that the adult CF mice (age, 6-12 weeks) did not exhibit CFTR-dependent Cl-secretion; however, they did have a partial CFTR-independent duodenal HCO3- secretion in response to CCh (17). Therefore, CaCC may have an important role in the regulation of intestinal Cl-secretion in young CF mice and may be important for duodenal HCO3- secretion in adult CF mice.

The Ca2+-activated TMEM16A anion channel (or anoctamin 1) was reported to be able to conduct HCO3- upon a significant increase in cytosolic Ca2+ levels (80). However, the role of anoctamin 1 in GI epithelial anion secretion remains under debate (81). More recently, a study by the current researchers indicated that caffeine-stimulated Ca2+-dependent duodenal anion secretion was attenuated by niflumic acid and T16Ainh-A01, two selective CaCC blockers with different chemical structures, suggesting that the TMEM16A anion channel is likely one of the downstream effectors of Ca2+ signaling (82).

It has been demonstrated that a residual cholinergic Cl- secretion was preserved in a subset of patients with CF with a mild phenotype (83). In T84 colonic carcinoma cells, the role of CaCC has also been characterized and it was indicated to be responsible for Ca2+-mediated Cl-secretion in these cells (83). However, other studies suggested that the integrated function of CFTR is important for CaCC (84), as Ca2+-dependent cholinergic Cl- secretion was able to be completely inhibited by the deactivation of CFTR (85). All those results suggest that residual cholinergic Cl-secretion in CF tissues depends on the residual function of mutant CFTR. Therefore, although there is evidence for an alternative CaCC in the mouse colon and human colonic carcinoma cell lines, the promotion by CaCC is probably limited (86).

Apical anion/HCO3-exchangers

It has been generally accepted that HCO3- secretion from the upper GI tract is important for the protection of normal mucosa (87). There are three anion/HCO3- exchangers: Solute carrier family 26 member 6 [SLC26A6; also known as putative anion transporter 1 (PAT1)], DAR and SLC4A9 (also known as anion exchange protein 4); all those channels contribute to the DBS to resist various aggressive factors, such as the acidic gastric output (88,89). However, at least three distinct mechanisms of HCO3- secretion have been described in the distal colon of rats (90,91): i) Cl-dependent: The HCO3- secretion mediated by a brush-border Cl-/HCO3- exchange; ii) SCFA-dependent: HCO3- secretion as a result of activation of SCFA/HCO3- exchange; and iii) cAMP-induced: HCO3- secretion associated with a CFTR (91).

As Cl-/HCO3- exchanger was expressed on the apical membrane of the small intestinal epithelium and likely has a role in secretagogue-stimulated DBS (92,93), its possible involvement in estrogen-stimulated DBS was assessed in a study by the current researchers (94). The results suggested that estradiol (E2) indeed stimulated murine DBS, which was attenuated by 4,4'-diisothiocyanostilbene-2-2'-disulfonic acid, a commonly used inhibitor of Cl-/HCO3- exchanger. E2 was also able to increase [Ca2+]cyt in duodenal epithelial cells expressing estrogen receptor, whereas 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM) one of an intracellular calcium chelator inhibited the E2-stimulated murine DBS. It was therefore suggested that the activation of estrogen receptor stimulates the Ca2+-dependent DBS via Cl-/HCO3- exchanger.

Colonic bicarbonate secretion (CBS) is closely linked to electrolyte movement and overall fluid in the colon (59). As mentioned earlier, CaSR activation increases [Ca2+]cyt; however, it decreases intracellular cAMP production. Consistently, Tang et al (59) reported that CaSR activation inhibited cAMP-activated CBS; however, it increased the lumen Cl-- and SCFA-dependent CBS. Consequently, upon activation of electroneutral Cl-/HCO3- and SCFA/HCO3- exchangers, CaSR stimulated CBS; by contrast, if forskolin-stimulated electrogenic CFTR-mediated HCO3- conductance dominated, CaSR inhibited CBS. Consistently with the results on the Ca2+-mediated regulation of Cl-/HCO3- exchanger-mediated DBS reported by the current researchers (13), these results further suggest a critical role of Ca2+ signaling in the regulation of Cl-/HCO3- and SCFA/HCO3- exchanger-mediated CBS (59). Therefore, modulation of CaSR activity may provide a new therapeutic approach to correct HCO3- deficits and metabolic acidosis, a primary cause of morbidity and mortality in acute infectious diarrheal illnesses (59). However, Lamprecht et al (95) reported on Ca2+-mediated inhibition of colonic DRA. Both the calcium ionophore A23187 and UTP that increased Ca2+ were able to inhibit DRA in these cells.

Basolateral store-operated channels and stromal interaction molecule (STIM)/Orai calcium release-activated calcium modulators. Store-operated calcium channels (SOC) are a major pathway for calcium signaling in virtually all mammalian cells and involved a variety of functions, including gene expression, cell growth and organ development (96-98). The SOC is stimulated by the diverse set of surface receptors via depletion of the Ca2+ concentration from the ER (99). The stromal interaction molecule (STIM) proteins were identified as the ER Ca2+ sensors and the Orai proteins as store-operated channels and since then, rapid progress has been made in the elucidation of the unique mechanisms of store-operated calcium entry (SOCE) (99). The role of STIM1/Orai signaling was previously studied mostly in nonpolarized cells, such as lymphocytes (100,101) or nonconfluent 293 cells (102,103). However, only a few studies have assessed the function of STIM1/Orai signaling in polarized GI epithelia (104-106). In the human colonic tumor cell line NCM460, STIM1 stimulated by the emptying of intracellular Ca2+ stores after the production of cAMP (104). In addition, in the intestinal epithelial cell (IEC)-6 cell line from rat intestinal crypts, STIM1/Orai was indicated to have a role in wound healing (105). In the rat colonic epithelium, STIM1/Orai was identified as a key component of intracellular Ca2+ signaling involved in the regulation of both apical and basolateral Ca2+ influx (106).

Although the critical role of Ca2+ signaling in GI epithelial anion secretion is well-known (13), the mechanisms by which [Ca2+]cyt homeostasis in GI epithelial cells is controlled remain to be fully elucidated (11). Under normal physiological conditions, in non-excitable epithelial cells, the occurrence of Ca2+ entry mainly depends on the SOC (99). In non-excitable cells, agonists induce Ca2+ signaling mostly depending on the intracellular Ca2+ release mainly from the ER and Ca2+ influx from the extracellular medium (107). IP3-sensitive and ryanodine-sensitive Ca2+ stores have been identified within the ER (108,109). The former is activated by the binding of IP3 to IP3R, while the latter is activated by the binding of ryanodine to RyR to induce ER Ca2+ release into the cytosol (110).

The IP3R-mediated Ca2+ influx pathway was reported to have a role in the regulation of GI epithelial anion secretion (109,111). Similarly, a study by the current researchers indicated that muscarinic receptors were activated after the application of CCh and induced mouse intestinal Cl- secretion, which was significantly inhibited by selective SOC blockers added to the serosal side of duodenal tissues in a Ca2+-free serosal solution (82). Furthermore, the study revealed that calcium release-activated calcium/Orai channels may represent the molecular candidate of SOC involved in the CCh-induced increase of intracellular Ca2+ in GI epithelium. As the underlying mechanisms of RyR-mediated ER Ca2+ release as an important component of SOCE to contribute to GI epithelial anion secretion had remained elusive, the role of RyR/Ca2+ storage was also further investigated by Dong et al (82). The results suggested that caffeine, a selective RyR activator, markedly increased mouse intestinal Cl- and HCO3- secretion. However, this process was suppressed by Ca2+-free serosal solutions and selective blockers of SOC/Ca2+ and knockdown of the protein expression of Orai1 channels also inhibited the Cl- and HCO3- secretion on the serosal side of duodenal tissue. Furthermore, the caffeine-induced anion secretion was inhibited by ER Ca2+ chelator and RyR blockers (82). In addition, the protein expression of STIM1 and Orai1 was detected. In IEC cells, the caffeine-induced SOCE was attenuated by selective SOC inhibitor (82).

It was therefore concluded that the RyR/Orai1/Ca2+ signaling on the basolateral side has a critical role in the regulation of GI epithelial anion secretion (67). Lefkimmiatis et al (112) indicated that in a newly identified type of SOC termed ‘store-operated cAMP signaling’ (SOcAMPS), the luminal ER Ca2+ sensor STIM1 does not depend on changes in [Ca2+]cyt. The decreasing free Ca2+ concentration within the ER lumen induces a rise in intracellular cAMP. Therefore, they proposed the SOcAMPS, in which the content of internal Ca2+ stores is directly connected to cAMP signaling through a process that involves STIM1. Subsequently, Nichols et al (113) determined that in T84 colonic cells, the Isc, cAMP and PKA activity was increased under Ca2+-free conditions after treatment with Ca2+-releasing agonist CCh and Ca2+ ionophore and suppressed by pre-treatment with BAPTA-AM. Furthermore, the effects of ER Ca2+ store depletion on cAMP/PKA activity were attenuated by Ca2+ entering from the extracellular space, indicating that the production of cAMP decreased after Ca2+ influx. They proposed that a discrete component of the ‘Ca2+-dependent’ secretory activity in the colon is derived from cAMP generated through SOcAMPS. These studies further support the notion that Ca2+ and cAMP signaling may independently trigger epithelial ion transport.

Basolateral Ca2+-activated K+ channels (Kca)

In GI epithelial cells, K+ channels are important in the intestinal epithelium, contribute to the stabilization of membrane voltage and provide the driving force for electrogenic anion transport (114). The concept that cholinergic agents promote the intestinal Cl- secretion via the activation of membrane K+ conductance and maintain the cellular Cl- transport has been widely accepted (115). Certain cholinergic agents, such as CCh, activate muscarinic receptors or acetylcholine raises the [Ca2+]cyt, which activates KCa conductance and secondarily stimulates Cl- secretion via the apical CFTR (116). Therefore, basolateral K+ channels hyperpolarize apical membrane potential and increase the electrical driving force for anion (Cl- and HCO3-) secretion to maintain electroneutrality.

To date, three different subtypes of KCa channels expressed on colonic surface and crypt cells have been identified: Large-conductance KCa channels, intermediate-conductance KCa channels (IKCa) and small-conductance KCa channels (117,118). Among them, IKCa channels have an important role in epithelial Cl- secretion. A selective blocker of IKCa channels, clotrimazole, inhibited the Cl- secretion in intact colonic epithelium and human colonic T84 cells (119). In addition, it has been demonstrated that activation of CFTR alone is insufficient to evoke transepithelial Cl- secretion and that basolateral membrane K+ channels are also necessary components of the secretory response (30). Therefore, basolateral membrane KCa channels represent an important potential therapeutic target to increase Cl- secretion in patients with CF.

While the expression and function of KCa channels and their role in the regulation of duodenal epithelial ion transport and DBS in the duodenal epithelium have remained elusive, it is well known that [Ca2+]cyt has an important role in epithelial ion transport (2,11); however, the underlying mechanisms of [Ca2+]cyt to induce duodenal HCO3- secretion, or indeed other ion transport systems, had not been explored in detail. Therefore, the functionality of Kca and their role in the regulation of duodenal mucosal ion transport were explored. A previous review by the current researchers provided evidence that IKCa or intermediate conductance calcium-activated potassium channel protein 4/SK4 channels are located on the basolateral side of duodenal epithelial cells and are involved in the regulation of Ca2+-mediated duodenal Cl- and HCO3- secretion (120). Furthermore, it was indicated that clotrimazole, a selective blocker of basolateral IKCa, was able to inhibit Ca2+-mediated duodenal Cl- and HCO3- secretion, suggesting its potential utility as an anti-diarrheal drug for the treatment of secretory diarrhea (13,121).

NCX

The plasma membrane NCX is an important membrane transporter and has a critical role in the maintenance of Ca2+ homeostasis in a variety of tissue types (122).

NCX is a bidirectional plasma membrane transporter and in each cycle, three Na+ for one Ca2+ are transported in the opposite direction and this process depends on electrochemical gradients (123). The expression and function of NCX have been demonstrated in cardiomyocytes, vascular cells and neurons (124). They are able to function in a forward mode to excrete intracellular Ca2+ and in reverse mode to induce extracellular Ca2+ entry and various associated signal transduction pathways (124). NCX was previously reported to be expressed in small intestinal epithelial cells and to function in the forward mode that is involved in the absorption of Ca2+ into the bloodstream. However, NCX also has a role in GI epithelial anion secretion (125).

Seip et al (126), demonstrated an interaction between SOC and NCX in the rat colon, where the influx of Na+ across SOC serves to reduce the driving force for Ca2+ extrusion via the NCX and thereby maintains the increase in [Ca2+]cyt during the induction of rat colonic anion secretion. Consistently, Kocks et al (110) reported a cross-talk between the depletion of intracellular Ca2+ stores and NCX, which may maintain a long-lasting increase in [Ca2+]cyt to amplify Ca2+-dependent colonic Cl- secretion. While it was demonstrated that muscarinic receptor induced the activation of [Ca2+]cyt increases, which regulates anion secretion, the underlying mechanisms of Ca2+ remained largely elusive. A previous study by the current researchers determined whether NCX has a role in the regulation of duodenal mucosal anion secretion by controlling Ca2+ homeostasis (127). The results indicated that activation of muscarinic receptors stimulated NCX activity in a reverse mode to increase [Ca2+]cyt in epithelial cells, leading to Ca2+-dependent HCO3- and Cl- secretion (127). In conclusion, NCX has an important role in Ca2+-dependent anion secretion by controlling Ca2+ homeostasis in GI epithelial cells.

4. Associated GI diseases

Ulcers

Ulcers refer to mucosal injury reaching the submucosa in the GI tract (128). Peptic ulcers may develop in the stomach or proximal duodenum and at the margin of a gastroenterostomy, Meckel's diverticulum or the esophagus (128). Helicobacter pylori (H. pylori) infection, non-steroidal anti-inflammatory drugs and stress cause a large proportion of peptic ulcers (129). Since patients with ulcers usually have hyperchlorhydria, proton-pump inhibitors are used to inhibit gastric acid secretion, besides eradication of H. pylori infection with antibiotics (130). It is well established that GI epithelial HCO3- secretion is critical for defending the vulnerable epithelium against various aggressive factors (87). The mucus secreted on the surface of GI mucosa and the bicarbonate ions secreted by the GI epithelium form a mucous bicarbonate barrier (87). When H+ in gastric acid diffuses to the stomach wall, it is neutralized by HCO3- secreted by epithelial cells (87). In this way, the surface of the gastric mucosa remains in a neutral or partially alkaline state, preventing gastric acid and pepsin from attacking the mucosa (131). The esophagus also requires HCO3- secretion to protect the epithelial surface from acid reflux (132). Furthermore, normal mucus release from GI epithelium requires concurrent HCO3- secretion, which is essential for the release of mucin molecules and their proper expansion on the surface of epithelium as well (133). As a matter of fact, DBS, as an important protector, has been confirmed in patients with duodenal ulcer whose acid-stimulated DBS is only 41% of that of healthy subjects (94). The defect in intestinal HCO3- secretion has further been indicated to be a risk factor for peptic ulcer diseases (134).

Additionally, normal colonic HCO3- secretion is critical for the mucosal defense against bacteria in the lower GI tract (87). The luminal pH was indicated to be acidic in the colon of patients with ulcerative colitis (UC), which may be caused at least in part by disturbances in the ion transport in the inflamed colon (135). Therefore, it appears important to recover normal GI epithelial HCO3- secretion in patients with peptic ulcers and inflamed colon to prevent their recurrence. It is of growing interest to discover novel drugs to stimulate sufficient GI epithelial HCO3- secretion for mucosal protection as a potential adjuvant therapy for ulcer diseases or prevention of their recurrence.

CF

Epithelial HCO3- secretion is impaired in the GI tract of patients with CF, suggesting a pivotal role of the CFTR in mediating epithelial HCO3- secretion (64). Patients with CF usually have an epithelial HCO3- deficit. As discussed earlier, while the CFTR is mainly triggered by the cAMP/PKA pathway, most of the channels involved in GI epithelial anion secretion, including CaCC, anion exchangers, KCa and even CFTR, may be generally triggered by Ca2+ signaling (136). For instance, the CaCC is stimulated by Ca2+ ionophores and Ca2+-mobilizing secretagogues in luminal membranes of GI epithelia from subjects with or without CF (136), including ACh, CCh, histamine, bradykinin, ATP and UTP (77,78). Furthermore, a previous study by the current researchers demonstrated that adult CF mice exhibited a partial CFTR-independent duodenal HCO3- secretion in response to CCh, although they did not display CFTR-dependent Cl-secretion (58). More recently, a study by the current researchers demonstrated that caffeine stimulated Ca2+-dependent duodenal anion secretion, which was able to be attenuated by selective CaCC blockers, suggesting that the CaCC is one of the downstream effectors of Ca2+ signaling (82). Therefore, after the cAMP-activated CFTR is impaired in CF, targeting the Ca2+-mediated pathway may be a potential adjuvant for CF therapy. Calcium ions have a critical role in the normal functioning of the gastrointestinal system (137). Certain calcium channel blockers were used to affect all of the organs of the gastrointestinal tract and may have therapeutic efficacy against esophageal spasm, mesenteric vascular insufficiency, irritable bowel syndrome, dyskinesis of the Sphincter of Oddi and insulinoma (137); however, this requires further intensive investigation.

Inflammatory bowel disease (IBD)

IBD, including Crohn's disease and UC, is a group of chronic inflammatory disorders of the GI tract. Diarrhea is the most highly prevalent and debilitating symptom of IBD (138). The pathogenesis of IBD is multifactorial and involves variations in patients' genome, immune response, the intestinal microbiome and environmental factors to result in an excessive and abnormal host immune response (139). However, the change of expression and/or function of epithelial ion channels and transporters may result in electrolyte retention and water accumulation in the intestinal lumen, leading to diarrhea in IBD (139). IBD is a chronic inflammatory disorder with high complex endogenous inflammatory meditators, including IL-1β, tumor necrosis factor-α, interferon-γ, IL-6, monochloramine and nitric oxide (140). They may act on intestinal epithelial ion transport and smooth muscle (141). Furthermore, the colon of patients with UC has an acidic luminal pH, which impairs the ion transport in the inflamed colon (142). Consistently, the expression of Cl-/HCO3- exchanger SLC26A3 (DRA) was reported to be markedly decreased in the inflamed colon (143). The expression of DRA was also indicated to be absent exclusively in UC patients, indicating inadequate membrane trafficking events (144,145). Furthermore, in a recent genome-wide association study, a single-nucleotide polymorphism in the SLC26A3 gene was identified as a risk factor for UC development (146). A strong reduction in Cl- absorption was identified in parallel with a low expression of DRA in UC colonic crypts (147). Therefore, decreased DRA expression may lead to a deficient Cl- absorption in UC, which emphasizes the important role of DRA in UC-associated diarrhea (148).

Congenital chloride diarrhea (CLD)

It is well established that DRA and PAT-1 are the two major transporters involved in apical Cl-/HCO3- exchange in the GI tract (88,90). As mentioned above, loss of the expression and function of DRA may induce diarrheal disorders (143). However, mutations in the DRA gene that encode Cl-/HCO3- exchange cause a rare diarrheal disorder named CLD, which is associated with a high stool concentration of Cl-, metabolic alkalosis and physiologic evidence of an absence of Cl-/HCO3- exchange in the colon and ileum (149). Therefore, the characteristics of patients with CLD include voluminous diarrhea, massive loss of Cl- via the stool and metabolic alkalosis. Furthermore, the pH of the ileocolonic lumen in patients with IBD has been reported to be reduced due to limited HCO3- secretion (146). Since DRA serves as the major luminal intestinal Cl-/HCO3- exchanger responsible for bulk intestinal Cl- absorption and HCO3- secretion, DRA deficiency is one of the important factors in the pathogenesis CLD and IBD (147). Therefore, based on the reported Ca2+-mediated inhibition of colonic DRA, it may be speculated that inhibition of intracellular Ca2+ signaling may have therapeutic potential to improve excessive fluid secretion, thereby providing a novel research direction for the treatment of CLD and IBD.

5. Conclusion

GI epithelial anion and fluid transport have critical roles in maintaining normal physiological functions in the GI tract. Defective GI epithelial anion secretion has been critically implicated in the pathophysiology of ulcer diseases, CF, intestinal inflammation, diarrhea/constipation and even metabolic acidosis. Similarly, [Ca2+]cyt also has a critical role in the regulation of digestive functions. GI epithelial anion secretion is known to be controlled by several neuro-humoral factors, including PGE2, ACh and 5-HT. These factors mediate epithelial anion secretion mainly through Ca2+, cAMP and cGMP signaling pathways. Although multiple interactions exist between Ca2+ signaling and the cAMP pathway to trigger GI epithelial anion secretion, growing lines of evidence indicated that Ca2+ signaling may mediate epithelial anion secretion in a cAMP-independent manner. Ca2+ signaling modulates GI epithelial anion secretion through acting on CFTR, CaCC, Cl-/HCO3- exchanger, SOC, Kca and NCX. It was previously assumed that those channels and transporters involved in GI epithelial secretion of Cl- and HCO3- are identical; however, emerging evidence suggests they are different. While cAMP may be a critical factor in CFTR-mediated Cl- secretion, Ca2+ signaling may have a critical role in Cl-/HCO3--mediated HCO3- secretion. Elucidation of the precise regulatory mechanisms of Ca2+-mediated GI epithelial Cl- and HCO3- secretion will markedly enhance the current knowledge of ion and fluid transport in the GI tract. Further investigation on the differences between GI epithelial secretion of Cl- and HCO3- may provide novel potential drug targets to protect the upper GI tract against ulcer diseases and promote epithelial HCO3- secretion.

Acknowledgements

The authors thank Professor Biguang Tuo (Department of Gastroenterology, Affiliated Hospital to Zunyi Medical University, Zunyi, China) for his assistance with the grammar, spelling and formatting of the manuscript.

Funding

The current study was supported by research grants of the National Natural Science Foundation of China (no. 81660412 to RX and no. 81970541 to JYX).

Availability of data and materials

Not applicable.

Authors' contributions

WS, YH, JD, XY, JL, QD, QL and LL conceived the current review article. JX and RX were responsible for the collection and assembly of the articles/published data for inclusion and interpretation in this review. All authors were involved in the writing of the manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Berridge MJ, Lipp P and Bootman MD: The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 1:11–21. 2000.PubMed/NCBI View Article : Google Scholar

2 

Clapham DE: Calcium signaling. Cell. 131:1047–1058. 2007.PubMed/NCBI View Article : Google Scholar

3 

Kristián T and Siesjö BK: Calcium in ischemic cell death. Stroke. 29:705–718. 1998.PubMed/NCBI View Article : Google Scholar

4 

Berridge MJ, Bootman MD and Roderick HL: Calcium signalling: Dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 4:517–529. 2003.PubMed/NCBI View Article : Google Scholar

5 

Dong Z, Saikumar P, Weinberg JM and Venkatachalam MA: Calcium in cell injury and death. Annu Rev Pathol. 1:405–434. 2006.PubMed/NCBI View Article : Google Scholar

6 

Romac JM, Shahid RA, Swain SM, Vigna SR and Liddle RA: Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis. Nat Commun. 9(1715)2018.PubMed/NCBI View Article : Google Scholar

7 

Criddle DN, McLaughlin E, Murphy JA, Petersen OH and Sutton R: The pancreas misled: Signals to pancreatitis. Pancreatology. 7:436–446. 2007.PubMed/NCBI View Article : Google Scholar

8 

Lee PJ and Papachristou GI: New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol. 16:479–496. 2019.PubMed/NCBI View Article : Google Scholar

9 

Karlstad J, Sun Y and Singh BB: Ca(2+) signaling: An outlook on the characterization of Ca(2+) channels and their importance in cellular functions. Adv Exp Med Biol. 740:143–157. 2012.PubMed/NCBI View Article : Google Scholar

10 

Kinjo TG and Schnetkamp PPM: Ca2+ chemistry, storage and transport in biologic systems: An overview. Mol Biol Intell Unit, pp1-11, 1970.

11 

Foskett JK, White C, Cheung KH and Mak DO: Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev. 87:593–658. 2007.PubMed/NCBI View Article : Google Scholar

12 

He J, Yang X, Guo Y, Zhang F, Wan H, Sun X, Tuo B and Dong H: Ca2+ signaling in HCO3- secretion and protection of upper GI tract. Oncotarget. 8:102681–102689. 2017.PubMed/NCBI View Article : Google Scholar

13 

Xie R, Dong X, Wong C, Vallon V, Tang B, Sun J, Yang S and Dong H: Molecular mechanisms of calcium-sensing receptor-mediated calcium signaling in the modulation of epithelial ion transport and bicarbonate secretion. J Biol Chem. 289:34642–34653. 2014.PubMed/NCBI View Article : Google Scholar

14 

Abdulnour-Nakhoul S, Nakhoul HN, Kalliny MI, Gyftopoulos A, Rabon E, Doetjes R, Brown K and Nakhoul NL: Ion transport mechanisms linked to bicarbonate secretion in the esophageal submucosal glands. Am J Physiol Regul Integr Comp Physiol. 301:R83–R96. 2011.PubMed/NCBI View Article : Google Scholar

15 

Kiela PR and Ghishan FK: Physiology of intestinal absorption and secretion. Best Pract Res Clin Gastroenterol. 30:145–159. 2016.PubMed/NCBI View Article : Google Scholar

16 

Bachmann O and Seidler U: News from the end of the gut-how the highly segmental pattern of colonic HCO3- transport relates to absorptive function and mucosal integrity. Biol Pharm Bull. 34:794–802. 2011.PubMed/NCBI View Article : Google Scholar

17 

Yang X, Wen G, Tuo B, Zhang F, Wan H, He J, Yang S and Dong H: Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion. Oncotarget. 9:3727–3740. 2017.PubMed/NCBI View Article : Google Scholar

18 

Tuo B, Wen G, Zhang Y, Liu X, Wang X, Liu X and Dong H: Involvement of phosphatidylinositol 3-kinase in cAMP- and cGMP-induced duodenal epithelial CFTR activation in mice. Am J Physiol Cell Physiol. 297:C503–C515. 2009.PubMed/NCBI View Article : Google Scholar

19 

Ahuja M, Jha A, Maléth J, Park S and Muallem S: cAMP and Ca²+ signaling in secretory epithelia: Crosstalk and synergism. Cell Calcium. 55:385–393. 2014.PubMed/NCBI View Article : Google Scholar

20 

Lee RJ and Foskett JK: cAMP-activated Ca2+ signaling is required for CFTR-mediated serous cell fluid secretion in porcine and human airways. J Clin Invest. 120:3137–3148. 2010.PubMed/NCBI View Article : Google Scholar

21 

Kallenberg LA: Calcium signalling in secretory cells. Arch Physiol Biochem. 108:385–390. 2000.PubMed/NCBI View Article : Google Scholar

22 

Lee MG, Ohana E, Park HW, Yang D and Muallem S: Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev. 92:39–74. 2012.PubMed/NCBI View Article : Google Scholar

23 

Ambudkar IS: Ca²+ signaling and regulation of fluid secretion in salivary gland acinar cells. Cell Calcium. 55:297–305. 2014.PubMed/NCBI View Article : Google Scholar

24 

Linan-Rico A, Ochoa-Cortes F, Beyder A, Soghomonyan S, Zuleta-Alarcon A, Coppola V and Christofi FL: Mechanosensory signaling in enterochromaffin cells and 5-HT release: Potential implications for gut inflammation. Front Neurosci. 10(564)2016.PubMed/NCBI View Article : Google Scholar

25 

Thiagarajah JR, Donowitz M and Verkman AS: Secretory diarrhoea: Mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol. 12:446–457. 2015.PubMed/NCBI View Article : Google Scholar

26 

Chen M, Praetorius J, Zheng W, Xiao F, Riederer B, Singh AK, Stieger N, Wang J, Shull GE, Aalkjaer C and Seidler U: The electroneutral Na+:HCO3 cotransporter NBCn1 is a major pHi regulator in murine duodenum. J Physiol. 590:3317–3333. 2012.PubMed/NCBI View Article : Google Scholar

27 

Frizzell RA and Hanrahan JW: Physiology of epithelial chloride and fluid secretion. Cold Spring Harb Perspect Med. 2(a009563)2012.PubMed/NCBI View Article : Google Scholar

28 

Quinton PM: Role of epithelial HCO3- transport in mucin secretion: Lessons from cystic fibrosis. Am J Physiol Cell Physiol. 299:C1222–C1233. 2010.PubMed/NCBI View Article : Google Scholar

29 

Furukawa O, Bi LC, Guth PH, Engel E, Hirokawa M and Kaunitz JD: NHE3 inhibition activates duodenal bicarbonate secretion in the rat. Am J Physiol Gastrointest Liver Physiol. 286:G102–G109. 2004.PubMed/NCBI View Article : Google Scholar

30 

Saint-Criq V and Gray MA: Role of CFTR in epithelial physiology. Cell Mol Life Sci. 74:93–115. 2017.PubMed/NCBI View Article : Google Scholar

31 

Yang N, Garcia MA and Quinton PM: Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis. J Physiol. 591:4581–4593. 2013.PubMed/NCBI View Article : Google Scholar

32 

Chávez JC, Hernández-González EO, Wertheimer E, Visconti PE, Darszon A and Treviño CL: Participation of the Cl-/HCO(3)-exchangers SLC26A3 and SLC26A6, the Cl- channel CFTR, and the regulatory factor SLC9A3R1 in mouse sperm capacitation. Biol Reprod. 86:1–14. 2012.PubMed/NCBI View Article : Google Scholar

33 

Hug MJ, Tamada T and Bridges RJ: CFTR and bicarbonate secretion by [correction of to] epithelial cells. News Physiol Sci. 18:38–42. 2003.PubMed/NCBI View Article : Google Scholar

34 

Binder HJ, Rajendran V, Sadasivan V and Geibel JP: Bicarbonate secretion: A neglected aspect of colonic ion transport. J Clin Gastroenterol. 39 (4 Suppl 2):S53–S58. 2005.PubMed/NCBI View Article : Google Scholar

35 

Feldman M: Gastric bicarbonate secretion in humans. Effect of pentagastrin, bethanechol, and 11,16,16-trimethyl prostaglandin E2. J Clin Invest. 72:295–303. 1983.PubMed/NCBI View Article : Google Scholar

36 

Fei G, Fang X, Wang GD, Liu S, Wang XY, Xia Y and Wood JD: Neurogenic mucosal bicarbonate secretion in guinea pig duodenum. Br J Pharmacol. 168:880–890. 2013.PubMed/NCBI View Article : Google Scholar

37 

Rune SJ: pH in the human duodenum. Its physiological and pathophysiological significance. Digestion. 8:261–268. 1973.PubMed/NCBI View Article : Google Scholar

38 

Kuna L, Jakab J, Smolic R, Raguz-Lucic N, Vcev A and Smolic M: Peptic ulcer disease: A brief review of conventional therapy and herbal treatment options. J Clin Med. 8(179)2019.PubMed/NCBI View Article : Google Scholar

39 

Field M: Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest. 111:931–943. 2003.PubMed/NCBI View Article : Google Scholar

40 

Gennari FJ and Weise WJ: Acid-base disturbances in gastrointestinal disease. Clin J Am Soc Nephrol. 3:1861–1868. 2008.PubMed/NCBI View Article : Google Scholar

41 

Pratha VS, Hogan DL, Martensson BA, Bernard J, Zhou R and Isenberg JI: Identification of transport abnormalities in duodenal mucosa and duodenal enterocytes from patients with cystic fibrosis. Gastroenterology. 118:1051–1060. 2000.PubMed/NCBI View Article : Google Scholar

42 

Xiao F, Li J, Singh AK, Riederer B, Wang J, Sultan A, Park H, Lee MG, Lamprecht G, Scholte BJ, et al: Rescue of epithelial HCO3- secretion in murine intestine by apical membrane expression of the cystic fibrosis transmembrane conductance regulator mutant F508del. J Physiol. 590:5317–5334. 2012.PubMed/NCBI View Article : Google Scholar

43 

Ehre C, Ridley C and Thornton DJ: Cystic fibrosis: An inherited disease affecting mucin-producing organs. Int J Biochem Cell Biol. 52:136–145. 2014.PubMed/NCBI View Article : Google Scholar

44 

Wilschanski M and Novak I: The cystic fibrosis of exocrine pancreas. Cold Spring Harb Perspect Med. 3(a009746)2013.PubMed/NCBI View Article : Google Scholar

45 

Ramos AF, de Fuccio MB, Moretzsohn LD, Barbosa AJ, Passos Mdo C, Carvalho RS and Coelho LG: Cystic fibrosis, gastroduodenal inflammation, duodenal ulcer, and H. pylori infection: The ‘cystic fibrosis paradox’ revisited. J Cyst Fibros. 12:377–383. 2013.PubMed/NCBI View Article : Google Scholar

46 

Kuwahara A: Involvement of the gut chemosensory system in the regulation of colonic anion secretion. Biomed Res Int. 2015(403919)2015.PubMed/NCBI View Article : Google Scholar

47 

Markadieu N and Delpire E: Physiology and pathophysiology of SLC12A1/2 transporters. Pflugers Arch. 466:91–105. 2014.PubMed/NCBI View Article : Google Scholar

48 

Flores CA, Melvin JE, Figueroa CD and Sepúlveda FV: Abolition of Ca2+-mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca2+-dependent K+ channel Kcnn4. J Physiol. 583:705–717. 2007.PubMed/NCBI View Article : Google Scholar

49 

Mohammad-Panah R, Ackerley C, Rommens J, Choudhury M, Wang Y and Bear CE: The chloride channel ClC-4 co-localizes with cystic fibrosis transmembrane conductance regulator and may mediate chloride flux across the apical membrane of intestinal epithelia. J Biol Chem. 277:566–574. 2002.PubMed/NCBI View Article : Google Scholar

50 

Argenzio RA, Whipp SC and Glock RD: Pathophysiology of swine dysentery: Colonic transport and permeability studies. J Infect Dis. 142:676–684. 1980.PubMed/NCBI View Article : Google Scholar

51 

Lakhan SE and Kirchgessner A: Neuroinflammation in inflammatory bowel disease. J Neuroinflammation. 7(37)2010.PubMed/NCBI View Article : Google Scholar

52 

Park HW and Lee MG: Transepithelial bicarbonate secretion: Lessons from the pancreas. Cold Spring Harb Perspect Med. 2(a009571)2012.PubMed/NCBI View Article : Google Scholar

53 

Kaji I, Akiba Y, Said H, Narimatsu K and Kaunitz JD: Luminal 5-HT stimulates colonic bicarbonate secretion in rats. Br J Pharmacol. 172:4655–4670. 2015.PubMed/NCBI View Article : Google Scholar

54 

Sugamoto S, Kawauch S, Furukawa O, Mimaki TH and Takeuchi K: Role of endogenous nitric oxide and prostaglandin in duodenal bicarbonate response induced by mucosal acidification in rats. Dig Dis Sci. 46:1208–1216. 2001.PubMed/NCBI View Article : Google Scholar

55 

Devor DC, Singh AK, Lambert LC, DeLuca A, Frizzell RA and Bridges RJ: Bicarbonate and chloride secretion in Calu-3 human airway epithelial cells. J Gen Physiol. 113:743–760. 1999.PubMed/NCBI View Article : Google Scholar

56 

Condliffe SB, Doolan CM and Harvey BJ: 17beta-oestradiol acutely regulates Cl- secretion in rat distal colonic epithelium. J Physiol. 530:47–54. 2001.PubMed/NCBI View Article : Google Scholar

57 

Tuo B, Wen G, Wei J, Liu X, Wang X, Zhang Y, Wu H, Dong X, Chow JY, Vallon V and Dong H: Estrogen regulation of duodenal bicarbonate secretion and sex-specific protection of human duodenum. Gastroenterology. 141:854–863. 2011.PubMed/NCBI View Article : Google Scholar

58 

Yang X, Guo Y, He J, Zhang F, Sun X, Yang S and Dong H: Estrogen and estrogen receptors in the modulation of gastrointestinal epithelial secretion. Oncotarget. 8:97683–97692. 2017.PubMed/NCBI View Article : Google Scholar

59 

Tang L, Peng M, Liu L, Chang W, Binder HJ and Cheng SX: Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon. Am J Physiol Gastrointest Liver Physiol. 308:G874–G883. 2015.PubMed/NCBI View Article : Google Scholar

60 

Nathanson NM: Synthesis, trafficking, and localization of muscarinic acetylcholine receptors. Pharmacol Ther. 119:33–43. 2008.PubMed/NCBI View Article : Google Scholar

61 

Gustafsson JK, Lindén SK, Alwan AH, Scholte BJ, Hansson GC and Sjövall H: Carbachol-induced colonic mucus formation requires transport via NKCC1, K+ channels and CFTR. Pflugers Arch. 467:1403–1415. 2015.PubMed/NCBI View Article : Google Scholar

62 

Billet A and Hanrahan JW: The secret life of CFTR as a calcium-activated chloride channel. J Physiol. 591:5273–5278. 2013.PubMed/NCBI View Article : Google Scholar

63 

Jia Y, Mathews CJ and Hanrahan JW: Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A. J Biol Chem. 272:4978–4984. 1997.PubMed/NCBI View Article : Google Scholar

64 

Kiela PR and Ghishan FK: Ion transport in the intestine. Curr Opin Gastroenterol. 25:87–91. 2009.PubMed/NCBI View Article : Google Scholar

65 

Shah VS, Ernst S, Tang XX, Karp PH, Parker CP, Ostedgaard LS and Welsh MJ: Relationships among CFTR expression, HCO3- secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies. Proc Natl Acad Sci USA. 113:5382–5387. 2016.PubMed/NCBI View Article : Google Scholar

66 

Goodman BE and Percy WH: CFTR in cystic fibrosis and cholera: From membrane transport to clinical practice. Adv Physiol Educ. 29:75–82. 2005.PubMed/NCBI View Article : Google Scholar

67 

Deachapunya C and O'Grady SM: Regulation of chloride secretion across porcine endometrial epithelial cells by prostaglandin E2. J Physiol. 508:31–47. 1998.PubMed/NCBI View Article : Google Scholar

68 

Hoffmann EK, Lambert IH and Pedersen SF: Physiology of cell volume regulation in vertebrates. Physiol Rev. 89:193–277. 2009.PubMed/NCBI View Article : Google Scholar

69 

Borowitz D and Gelfond D: Intestinal complications of cystic fibrosis. Curr Opin Pulm Med. 19:676–680. 2013.PubMed/NCBI View Article : Google Scholar

70 

Kelly T and Buxbaum J: Gastrointestinal manifestations of cystic fibrosis. Dig Dis Sci. 60:1903–1913. 2015.PubMed/NCBI View Article : Google Scholar

71 

Lavelle GM, White MM, Browne N, McElvaney NG and Reeves EP: Animal models of cystic fibrosis pathology: Phenotypic parallels and divergences. Biomed Res Int. 2016(5258727)2016.PubMed/NCBI View Article : Google Scholar

72 

Li C, Dandridge KS, Di A, Marrs KL, Harris EL, Roy K, Jackson JS, Makarova NV, Fujiwara Y, Farrar PL, et al: Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions. J Exp Med. 202:975–986. 2005.PubMed/NCBI View Article : Google Scholar

73 

Rasmussen JE, Sheridan JT, Polk W, Davies CM and Tarran R: Cigarette smoke-induced Ca2+ release leads to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. J Biol Chem. 289:7671–7681. 2014.PubMed/NCBI View Article : Google Scholar

74 

Patel W, Moore PJ, Sassano MF, Lopes-Pacheco M, Aleksandrov AA, Amaral MD, Tarran R and Gray MA: Increases in cytosolic Ca2+ induce dynamin- and calcineurin-dependent internalisation of CFTR. Cell Mol Life Sci. 76:977–994. 2019.PubMed/NCBI View Article : Google Scholar

75 

He J, Yang X, Guo Y, Zhang F, Wan H, Sun X, Tuo B and Dong H: Ca2+ signaling in HCO3- secretion and protection of upper GI tract. Oncotarget. 8:102681–102689. 2017.PubMed/NCBI View Article : Google Scholar

76 

Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O and Galietta LJ: TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science. 322:590–594. 2008.PubMed/NCBI View Article : Google Scholar

77 

Zimmermann H: Extracellular ATP and other nucleotides-ubiquitous triggers of intercellular messenger release. Purinergic Signal. 12:25–57. 2016.PubMed/NCBI View Article : Google Scholar

78 

Beech DJ: Inhibitory effects of histamine and bradykinin on calcium current in smooth muscle cells isolated from guinea-pig ileum. J Physiol. 463:565–583. 1993.PubMed/NCBI View Article : Google Scholar

79 

Morris AP, Scott JK, Ball JM, Zeng CQ, O'Neal WK and Estes MK: NSP4 elicits age-dependent diarrhea and Ca(2+)mediated I(-) influx into intestinal crypts of CF mice. Am J Physiol. 277:G431–G444. 1999.PubMed/NCBI View Article : Google Scholar

80 

Yu K, Zhu J, Qu Z, Cui YY and Hartzell HC: Activation of the Ano1 (TMEM16A) chloride channel by calcium is not mediated by calmodulin. J Gen Physiol. 143:253–267. 2014.PubMed/NCBI View Article : Google Scholar

81 

Kunzelmann K, Ousingsawat J, Cabrita I, Doušová T, Bähr A, Janda M, Schreiber R and Benedetto R: TMEM16A in cystic fibrosis: Activating or inhibiting? Front Pharmacol. 10(3)2019.PubMed/NCBI View Article : Google Scholar

82 

Zhang F, Wan H, Yang X, He J, Lu C, Yang S, Tuo B and Dong H: Molecular mechanisms of caffeine-mediated intestinal epithelial ion transports. Br J Pharmacol. 176:1700–1716. 2019.PubMed/NCBI View Article : Google Scholar

83 

Kunzelmann K and Mall M: Electrolyte transport in the mammalian colon: mechanisms and implications for disease. Physiol Rev. 82:245–289. 2002.PubMed/NCBI View Article : Google Scholar

84 

Berg J, Yang H and Jan LY: Ca2+-activated Cl- channels at a glance. J Cell Sci. 125:1367–1371. 2012.PubMed/NCBI View Article : Google Scholar

85 

Zsembery A, Strazzabosco M and Graf J: Ca2+-activated Cl- channels can substitute for CFTR in stimulation of pancreatic duct bicarbonate secretion. FASEB J. 14:2345–2356. 2000.PubMed/NCBI View Article : Google Scholar

86 

Berkes J, Viswanathan VK, Savkovic SD and Hecht G: Intestinal epithelial responses to enteric pathogens: Effects on the tight junction barrier, ion transport, and inflammation. Gut. 52:439–451. 2003.PubMed/NCBI View Article : Google Scholar

87 

Flemström G and Isenberg JI: Gastroduodenal mucosal alkaline secretion and mucosal protection. News Physiol Sci. 16:23–28. 2001.PubMed/NCBI View Article : Google Scholar

88 

Simpson JE, Schweinfest CW, Shull GE, Gawenis LR, Walker NM, Boyle KT, Soleimani M and Clarke LL: PAT-1 (Slc26a6) is the predominant apical membrane Cl-/HCO3- exchanger in the upper villous epithelium of the murine duodenum. Am J Physiol Gastrointest Liver Physiol. 292:G1079–G1088. 2007.PubMed/NCBI View Article : Google Scholar

89 

Xiao F, Yu Q, Li J, Johansson ME, Singh AK, Xia W, Riederer B, Engelhardt R, Montrose M, Soleimani M, et al: Slc26a3 deficiency is associated with loss of colonic HCO3 (-) secretion, absence of a firm mucus layer and barrier impairment in mice. Acta Physiol (Oxf). 211:161–175. 2014.PubMed/NCBI View Article : Google Scholar

90 

Vidyasagar S, Barmeyer C, Geibel J, Binder HJ and Rajendran VM: Role of short-chain fatty acids in colonic HCO(3) secretion. Am J Physiol Gastrointest Liver Physiol. 288:G1217–G1226. 2005.PubMed/NCBI View Article : Google Scholar

91 

Vidyasagar S, Rajendran VM and Binder HJ: Three distinct mechanisms of HCO3- secretion in rat distal colon. Am J Physiol Cell Physiol. 287:C612–C621. 2004.PubMed/NCBI View Article : Google Scholar

92 

Singh AK, Riederer B, Chen M, Xiao F, Krabbenhöft A, Engelhardt R, Nylander O, Soleimani M and Seidler U: The switch of intestinal Slc26 exchangers from anion absorptive to HCOFormula secretory mode is dependent on CFTR anion channel function. Am J Physiol Cell Physiol. 298:C1057–C1065. 2010.PubMed/NCBI View Article : Google Scholar

93 

Singh AK, Liu Y, Riederer B, Engelhardt R, Thakur BK, Soleimani M and Seidler U: Molecular transport machinery involved in orchestrating luminal acid-induced duodenal bicarbonate secretion in vivo. J Physiol. 591:5377–5391. 2013.PubMed/NCBI View Article : Google Scholar

94 

Smith A, Contreras C, Ko KH, Chow J, Dong X, Tuo B, Zhang HH, Chen DB and Dong H: Gender-specific protection of estrogen against gastric acid-induced duodenal injury: Stimulation of duodenal mucosal bicarbonate secretion. Endocrinology. 149:4554–4566. 2008.PubMed/NCBI View Article : Google Scholar

95 

Lamprecht G, Hsieh CJ, Lissner S, Nold L, Heil A, Gaco V, Schäfer J, Turner JR and Gregor M: Intestinal anion exchanger down-regulated in adenoma (DRA) is inhibited by intracellular calcium. J Biol Chem. 284:19744–19753. 2009.PubMed/NCBI View Article : Google Scholar

96 

Feske S, Giltnane J, Dolmetsch R, Staudt LM and Rao A: Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol. 2:316–324. 2001.PubMed/NCBI View Article : Google Scholar

97 

Rosenberg SS and Spitzer NC: Calcium signaling in neuronal development. Cold Spring Harb Perspect Biol. 3(a004259)2011.PubMed/NCBI View Article : Google Scholar

98 

Stiber J, Hawkins A, Zhang ZS, Wang S, Burch J, Graham V, Ward CC, Seth M, Finch E, Malouf N, et al: STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nat Cell Biol. 10:688–697. 2008.PubMed/NCBI View Article : Google Scholar

99 

Prakriya M and Lewis RS: Store-operated calcium channels. Physiol Rev. 95:1383–1436. 2015.PubMed/NCBI View Article : Google Scholar

100 

Baba Y, Hayashi K, Fujii Y, Mizushima A, Watarai H, Wakamori M, Numaga T, Mori Y, Iino M, Hikida M and Kurosaki T: Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc Natl Acad Sci USA. 103:16704–16709. 2006.PubMed/NCBI View Article : Google Scholar

101 

Barr VA, Bernot KM, Srikanth S, Gwack Y, Balagopalan L, Regan CK, Helman DJ, Sommers CL, Oh-Hora M, Rao A and Samelson LE: Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: Puncta and distal caps. Mol Biol Cell. 19:2802–2817. 2008.PubMed/NCBI View Article : Google Scholar

102 

Smyth JT, Lemonnier L, Vazquez G, Bird GS and Putney JW Jr: Dissociation of regulated trafficking of TRPC3 channels to the plasma membrane from their activation by phospholipase C. J Biol Chem. 281:11712–11720. 2006.PubMed/NCBI View Article : Google Scholar

103 

Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS and Putney JW Jr: Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem. 281:24979–24990. 2006.PubMed/NCBI View Article : Google Scholar

104 

Lefkimmiatis K, Moyer MP, Curci S and Hofer AM: ‘cAMP sponge’: A buffer for cyclic adenosine 3', 5'-monophosphate. PLoS One. 4(e7649)2009.PubMed/NCBI View Article : Google Scholar

105 

Rao JN, Rathor N, Zou T, Liu L, Xiao L, Yu TX, Cui YH and Wang JY: STIM1 translocation to the plasma membrane enhances intestinal epithelial restitution by inducing TRPC1-mediated Ca2+ signaling after wounding. Am J Physiol Cell Physiol. 299:C579–C588. 2010.PubMed/NCBI View Article : Google Scholar

106 

Onodera K, Pouokam E and Diener M: STIM1-regulated Ca2+ influx across the apical and the basolateral membrane in colonic epithelium. J Membr Biol. 246:271–285. 2013.PubMed/NCBI View Article : Google Scholar

107 

Smyth JT, DeHaven WI, Bird GS and Putney JW Jr: Role of the microtubule cytoskeleton in the function of the store-operated Ca2+ channel activator STIM1. J Cell Sci. 120:3762–3771. 2007.PubMed/NCBI View Article : Google Scholar

108 

Seo MD, Enomoto M, Ishiyama N, Stathopulos PB and Ikura M: Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. Biochim Biophys Acta. 1853:1980–1991. 2015.PubMed/NCBI View Article : Google Scholar

109 

Putney JW Jr: Capacitative calcium entry revisited. Cell Calcium. 11:611–624. 1990.PubMed/NCBI View Article : Google Scholar

110 

Kocks S, Schultheiss G and Diener M: Ryanodine receptors and the mediation of Ca2+-dependent anion secretion across rat colon. Pflugers Arch. 445:390–397. 2002.PubMed/NCBI View Article : Google Scholar

111 

Prole DL and Taylor CW: Inositol 1,4,5-trisphosphate receptors and their protein partners as signalling hubs. J Physiol. 594:2849–2866. 2016.PubMed/NCBI View Article : Google Scholar

112 

Lefkimmiatis K, Srikanthan M, Maiellaro I, Moyer MP, Curci S and Hofer AM: Store-operated cyclic AMP signalling mediated by STIM1. Nat Cell Biol. 11:433–442. 2009.PubMed/NCBI View Article : Google Scholar

113 

Nichols JM, Maiellaro I, Abi-Jaoude J, Curci S and Hofer AM: ‘Store-operated’ cAMP signaling contributes to Ca2+-activated Cl- secretion in T84 colonic cells. Am J Physiol Gastrointest Liver Physiol. 309:G670–G679. 2015.PubMed/NCBI View Article : Google Scholar

114 

Julio-Kalajzić F, Villanueva S, Burgos J, Ojeda M, Cid LP, Jentsch TJ and Sepúlveda FV: K2P TASK-2 and KCNQ1-KCNE3 K+ channels are major players contributing to intestinal anion and fluid secretion. J Physiol. 596:393–407. 2018.PubMed/NCBI View Article : Google Scholar

115 

Assaha DVM, Ueda A, Saneoka H, Al-Yahyai R and Yaish MW: The role of Na+ and K+ transporters in salt stress adaptation in glycophytes. Front Physiol. 8(509)2017.PubMed/NCBI View Article : Google Scholar

116 

Wang J, Haanes KA and Novak I: Purinergic regulation of CFTR and Ca(2+)-activated Cl(-) channels and K(+) channels in human pancreatic duct epithelium. Am J Physiol Cell Physiol. 304:C673–C684. 2013.PubMed/NCBI View Article : Google Scholar

117 

Joiner WJ, Basavappa S, Vidyasagar S, Nehrke K, Krishnan S, Binder HJ, Boulpaep EL and Rajendran VM: Active K+ secretion through multiple KCa-type channels and regulation by IKCa channels in rat proximal colon. Am J Physiol Gastrointest Liver Physiol. 285:G185–G196. 2003.PubMed/NCBI View Article : Google Scholar

118 

Thompson-Vest N, Shimizu Y, Hunne B and Furness JB: The distribution of intermediate-conductance, calcium-activated, potassium (IK) channels in epithelial cells. J Anat. 208:219–229. 2006.PubMed/NCBI View Article : Google Scholar

119 

McNamara B, Winter DC, Cuffe JE, O'Sullivan GC and Harvey BJ: Basolateral K+ channel involvement in forskolin-activated chloride secretion in human colon. J Physiol. 519:251–260. 1999.PubMed/NCBI View Article : Google Scholar

120 

Du C, Chen S, Wan H, Chen L, Li L, Guo H, Tuo B and Dong H: Different functional roles for K+ channel subtypes in regulating small intestinal glucose and ion transport. Biol Open. 8(bio042200)2019.PubMed/NCBI View Article : Google Scholar

121 

Dong H, Smith A, Hovaida M and Chow JY: Role of Ca2+-activated K+ channels in duodenal mucosal ion transport and bicarbonate secretion. Am J Physiol Gastrointest Liver Physiol. 291:G1120–G1128. 2006.PubMed/NCBI View Article : Google Scholar

122 

Ottolia M and Philipson KD: NCX1: Mechanism of transport. Adv Exp Med Biol. 961:49–54. 2013.PubMed/NCBI View Article : Google Scholar

123 

Brini M and Carafoli E: The plasma membrane Ca2+ ATPase and the plasma membrane sodium calcium exchanger cooperate in the regulation of cell calcium. Cold Spring Harb Perspect Biol. 3(a004168)2011.PubMed/NCBI View Article : Google Scholar

124 

Lee SY and Kim JH: Mechanisms underlying presynaptic Ca2+ transient and vesicular glutamate release at a CNS nerve terminal during in vitro ischaemia. J Physiol. 593:2793–2806. 2015.PubMed/NCBI View Article : Google Scholar

125 

Liao QS, Du Q, Lou J, Xu JY and Xie R: Roles of Na+/Ca2+ exchanger 1 in digestive system physiology and pathophysiology. World J Gastroenterol. 25:287–299. 2019.PubMed/NCBI View Article : Google Scholar

126 

Seip G, Schultheiss G, Kocks SL and Diener M: Interaction between store-operated non-selective cation channels and the Na(+)-Ca(2+) exchanger during secretion in the rat colon. Exp Physiol. 86:461–468. 2001.PubMed/NCBI View Article : Google Scholar

127 

Dong H, Sellers ZM, Smith A, Chow JY and Barrett KE: Na(+)/Ca(2+) exchange regulates Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion in mice. Am J Physiol Gastrointest Liver Physiol. 288:G457–G465. 2005.PubMed/NCBI View Article : Google Scholar

128 

Narayanan M, Reddy KM and Marsicano E: Peptic ulcer disease and Helicobacter pylori infection. Mo Med. 115:219–224. 2018.PubMed/NCBI

129 

Iijima K, Kanno T, Koike T and Shimosegawa T: Helicobacter pylori-negative, non-steroidal anti-inflammatory drug: Negative idiopathic ulcers in Asia. World J Gastroenterol. 20:706–713. 2014.PubMed/NCBI View Article : Google Scholar

130 

Goderska K, Agudo Pena S and Alarcon T: Helicobacter pylori treatment: Antibiotics or probiotics. Appl Microbiol Biotechnol. 102:1–7. 2018.PubMed/NCBI View Article : Google Scholar

131 

Phan J, Benhammou JN and Pisegna JR: Gastric hypersecretory states: Investigation and management. Curr Treat Options Gastroenterol. 13:386–397. 2015.PubMed/NCBI View Article : Google Scholar

132 

Mejia A and Kraft WK: Acid peptic diseases: Pharmacological approach to treatment. Expert Rev Clin Pharmacol. 2:295–314. 2009.PubMed/NCBI View Article : Google Scholar

133 

Garcia MA, Yang N and Quinton PM: Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. J Clin Invest. 119:2613–2622. 2009.PubMed/NCBI View Article : Google Scholar

134 

Allen A and Flemström G: Gastroduodenal mucus bicarbonate barrier: Protection against acid and pepsin. Am J Physiol Cell Physiol. 288:C1–C19. 2005.PubMed/NCBI View Article : Google Scholar

135 

Barkas F, Liberopoulos E, Kei A and Elisaf M: Electrolyte and acid-base disorders in inflammatory bowel disease. Ann Gastroenterol. 26:23–28. 2013.PubMed/NCBI

136 

Hwang SJ, Basma N, Sanders KM and Ward SM: Effects of new-generation inhibitors of the calcium-activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract. Br J Pharmacol. 173:1339–1349. 2016.PubMed/NCBI View Article : Google Scholar

137 

Findling R, Frishman W, Javed MT, Heffer S and Brandt L: Calcium channel blockers and the gastrointestinal tract. Am J Ther. 3:383–408. 1996.PubMed/NCBI View Article : Google Scholar

138 

Zhang YZ and Li YY: Inflammatory bowel disease: Pathogenesis. World J Gastroenterol. 20:91–99. 2014.PubMed/NCBI View Article : Google Scholar

139 

Tanoue T, Umesaki Y and Honda K: Immune responses to gut microbiota-commensals and pathogens. Gut Microbes. 1:224–233. 2010.PubMed/NCBI View Article : Google Scholar

140 

Ghishan FK and Kiela PR: Epithelial transport in inflammatory bowel diseases. Inflamm Bowel Dis. 20:1099–1109. 2014.PubMed/NCBI View Article : Google Scholar

141 

Lau KS, Nakashima O, Aalund GR, Hogarth L, Ujiie K, Yuen J and Star RA: TNF-alpha and IFN-gamma induce expression of nitric oxide synthase in cultured rat medullary interstitial cells. Am J Physiol. 269:F212–F217. 1995.PubMed/NCBI View Article : Google Scholar

142 

Das S, Jayaratne R and Barrett KE: The role of ion transporters in the pathophysiology of infectious diarrhea. Cell Mol Gastroenterol Hepatol. 6:33–45. 2018.PubMed/NCBI View Article : Google Scholar

143 

Manoharan P, Coon S, Baseler W, Sundaram S, Kekuda R and Sundaram U: Prostaglandins, not the leukotrienes, regulate Cl(-)/HCO(3)(-) exchange (DRA, SLC26A3) in villus cells in the chronically inflamed rabbit ileum. Biochim Biophys Acta. 1828:179–186. 2013.PubMed/NCBI View Article : Google Scholar

144 

Yang D, Shcheynikov N, Zeng W, Ohana E, So I, Ando H, Mizutani A, Mikoshiba K and Muallem S: IRBIT coordinates epithelial fluid and HCO3- secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. J Clin Invest. 119:193–202. 2009.PubMed/NCBI View Article : Google Scholar

145 

Lohi H, Kujala M, Kerkelä E, Saarialho-Kere U, Kestilä M and Kere J: Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger. Genomics. 70:102–112. 2000.PubMed/NCBI View Article : Google Scholar

146 

Anbazhagan AN, Priyamvada S, Alrefai WA and Dudeja PK: Pathophysiology of IBD associated diarrhea. Tissue Barriers. 6(e1463897)2018.PubMed/NCBI View Article : Google Scholar

147 

Priyamvada S, Gomes R, Gill RK, Saksena S, Alrefai WA and Dudeja PK: Mechanisms underlying dysregulation of electrolyte absorption in inflammatory bowel disease-associated diarrhea. Inflamm Bowel Dis. 21:2926–2935. 2015.PubMed/NCBI View Article : Google Scholar

148 

Priyamvada S, Anbazhagan AN, Gujral T, Borthakur A, Saksena S, Gill RK, Alrefai WA and Dudeja PK: All-trans-retinoic acid increases SLC26A3 DRA (Down-regulated in Adenoma) expression in intestinal epithelial cells via HNF-1β. J Biol Chem. 290:15066–15077. 2015.PubMed/NCBI View Article : Google Scholar

149 

Seidler U and Nikolovska K: Slc26 Family of anion transporters in the gastrointestinal tract: Expression, function, regulation, and role in disease. Compr Physiol. 9:839–872. 2019.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

November-2020
Volume 20 Issue 5

Print ISSN: 1792-0981
Online ISSN:1792-1015

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Shan W, Hu Y, Ding J, Yang X, Lou J, Du Q, Liao Q, Luo L, Xu J, Xie R, Xie R, et al: Advances in Ca<sup>2+</sup> modulation of gastrointestinal anion secretion and its dysregulation in digestive disorders (Review). Exp Ther Med 20: 8, 2020.
APA
Shan, W., Hu, Y., Ding, J., Yang, X., Lou, J., Du, Q. ... Xie, R. (2020). Advances in Ca<sup>2+</sup> modulation of gastrointestinal anion secretion and its dysregulation in digestive disorders (Review). Experimental and Therapeutic Medicine, 20, 8. https://doi.org/10.3892/etm.2020.9136
MLA
Shan, W., Hu, Y., Ding, J., Yang, X., Lou, J., Du, Q., Liao, Q., Luo, L., Xu, J., Xie, R."Advances in Ca<sup>2+</sup> modulation of gastrointestinal anion secretion and its dysregulation in digestive disorders (Review)". Experimental and Therapeutic Medicine 20.5 (2020): 8.
Chicago
Shan, W., Hu, Y., Ding, J., Yang, X., Lou, J., Du, Q., Liao, Q., Luo, L., Xu, J., Xie, R."Advances in Ca<sup>2+</sup> modulation of gastrointestinal anion secretion and its dysregulation in digestive disorders (Review)". Experimental and Therapeutic Medicine 20, no. 5 (2020): 8. https://doi.org/10.3892/etm.2020.9136